To withstand assaults by viral pathogens, animals mount two types of immune responses following infection. An initial innate response acts both to limit pathogen growth and to prime the later adaptive response that generates cells and antibodies highly specific for a given pathogen. Innate effector cells such as natural killer (NK) cells recognize infection using germline-encoded receptors that detect molecular patterns common to subgroups of pathogens. These cells can also recognize infection or injury indirectly through receptors that detect "distress signals" displayed by damaged tissue. Understanding these receptors and their ligands would aid the production of agents that mimic or block those signals in the clinical setting. NKG2D is such a receptor expressed by all NK cells. It can trigger NK cell function in response to cells injured by viruses and other insults. In preliminary work, the applicant with his mentor and others have shown that NKG2D recognizes multiple ligands possessing very different gene expression patterns and binding kinetics. Herein, the applicant proposes to investigate the biological function of NKG2D ligands in relation to these differences in binding. This work is part of a career development plan. The specific aims of the investigation are: 1) to characterize the relationship between the binding kinetics of these ligands and their abilities to signal through NKG2D; 2) to determine whether viral infection preferentially induces cellsurface expression of the high-affinity and/or slowly-dissociating ligands; and 3) to demonstrate the role of NKG2D and its binding partners in viral infection in vivo. This career development program will provide the applicant with a transition to research independence. The applicant is a physician with a Ph.D. in immunology and biophysics. He is completing his fellowship training in pulmonary and critical care medicine at Washington University School of Medicine under the supervision of Dr. Wayne Yokoyama.